Low Foxp3+ regulatory T-cell (Treg) presence in the tumor-infiltrating lymphocytes (TILs) is considered favorable in breast cancer, and numerous CD25-targeting agents have been applied in the attempt to remove Foxp3+ Treg cells, which typically present CD4+ CD25+/hi surface phenotype. However, CD25 is not Treg-exclusive and can be upregulated by effector T cells. Hence, CD25 depletion may cause the elimination of activated T cells that are responding to tumor-specific antigens. In this study, the composition and function of CD4+ CD25+ cells inside the microenvironment of triple-negative breast carcinoma (TNBC) were investigated. Directly ex vivo, the Foxp3+ Treg cells represented a minor subset in total CD4+ CD25+ TILs. Significant differences were observed in the expression of Treg-associated molecules between CD4+ CD25+ Foxp3+ TILs and CD4+ CD25+ Foxp3- TILs. While both the CD4+ CD25+ Foxp3+ and the CD4+ CD25+ Foxp3- TILs could express CTLA-4 and LAG-3, the expression levels were significantly higher in CD4+ CD25+ Foxp3+ TILs than in CD4+ CD25+ Foxp3- TILs. Upon TCR stimulation, the expression of TGF-beta was significantly higher in CD4+ CD25+ Foxp3+ TILs, while the expression of IL-10 was significantly higher in CD4+ CD25+ Foxp3- TILs. These differences were conserved in the blood counterparts of these cells. Interestingly, the level of CD25+ Foxp3+ cells in circulating CD4+ T cells was positively correlated with the level of CD25+ Foxp3+ cells in CD4+ TILs, but the level of CD25+ Foxp3- cells in circulating CD4+ T cells was not associated with the level of CD25+ Foxp3- cells in CD4+ TILs. Th17-polarizing medium could readily remodel CD4+ CD25+ Foxp3- , but not CD4+ CD25+ Foxp3+ , T cells into RORgammat and IL-17-expressing T cells, demonstrating stronger plasticity of the former subset. Together, these data demonstrated that the CD4+ CD25+ TILs were composed of distinctive Foxp3- and Foxp3+ cells, with the former representing the major subset. The antigen specificity and effector molecule expression of the CD4+ CD25+ Foxp3- thus require further analyses.

中文翻译：

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三阴性乳腺癌浸润调节性T细胞的组成和可塑性。

在乳腺癌中，肿瘤浸润淋巴细胞（TIL）中Foxp3 +调节性T细胞（Treg）的含量低被认为是有利的，并且已尝试使用许多CD25靶向剂去除通常表现为CD4 + CD25 + /的Foxp3 + Treg细胞。嗨表面表型。但是，CD25不是Treg专有的，并且可以被效应T细胞上调。因此，CD25耗竭可能导致消除对肿瘤特异性抗原有反应的活化T细胞。在这项研究中，研究了三阴性乳腺癌（TNBC）微环境中CD4 + CD25 +细胞的组成和功能。直接离体，Foxp3 + Treg细胞仅占总CD4 + CD25 + TIL中的一小部分。在CD4 + CD25 + Foxp3 + TIL和CD4 + CD25 + Foxp3- TIL之间的Treg相关分子表达中观察到了显着差异。尽管CD4 + CD25 + Foxp3 +和CD4 + CD25 + Foxp3-TIL均可表达CTLA-4和LAG-3，但CD4 + CD25 + Foxp3 + TIL的表达水平明显高于CD4 + CD25 + Foxp3- TIL。在TCR刺激下，CD4 + CD25 + Foxp3 + TILs中TGF-beta的表达明显较高，而CD4 + CD25 + Foxp3- TILs中IL-10的表达明显较高。这些差异在这些细胞的血液对应物中得以保留。有趣的是，循环CD4 + T细胞中CD25 + Foxp3 +细胞的水平与CD4 + TILs中CD25 + Foxp3 +细胞的水平呈正相关，但是循环CD4 + T细胞中CD25 + Foxp3-细胞的水平与CD4 + TILs中CD25 + Foxp3-细胞的水平无关。Th17极化介质可以很容易地将CD4 + CD25 + Foxp3-重塑，但不能将CD4 + CD25 + Foxp3 +重塑成RORgammat和表达IL-17的T细胞，这表明前者具有更强的可塑性。这些数据加在一起表明，CD4 + CD25 + TIL由独特的Foxp3-和Foxp3 +细胞组成，前者代表主要子集。因此，需要进一步分析CD4 + CD25 + Foxp3-的抗原特异性和效应分子表达。这些数据表明，CD4 + CD25 + TIL由独特的Foxp3-和Foxp3 +细胞组成，前者代表主要亚群。CD4 + CD25 + Foxp3-的抗原特异性和效应分子表达因此需要进一步分析。这些数据表明，CD4 + CD25 + TIL由独特的Foxp3-和Foxp3 +细胞组成，前者代表主要亚群。因此，需要进一步分析CD4 + CD25 + Foxp3-的抗原特异性和效应分子表达。